We have described a preliminary genetic progression model that describes the timing of specific genetic events in head and neck squamous cell carcinoma progression. This model has included the nature and timing of loss and amplification at specific chromosomal loci that contain putative tumor suppressor genes and proto-oncogenes, respectively. Specific tumor suppressor genes, including p14 and p16, and proto-oncogenes, including p63, have been identified as critical in oral cancer development. This study builds upon the foundation of this prior model by identifying specific, ordered transcriptional alterations in order to establish a transcriptional progression model of oral cancer. The transcriptome of oral SCC described by this model will be correlated with DNA based SNP analysis to map and identify putative oncogenes and tumor suppressor genes. Specific attention will be directed at identification of early transcriptional and genetic alterations. These early molecular events will be identified and developed as targets for early detection and staging approaches, with emphasis on molecular detection strategies amenable to rapid, automated application.